Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. CD8 T cells play a crucial role in immunity to infections with intracellular pathogens. Upon stimulation, these T cells undergo a developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of antigen-specific effector T cell populations, followed by the persistence of long-lived memory T cells that mediate immunity to re-infection. The mechanisms underlying the generation and maintenance of memory CD8 T cells remain unclear. Previously we demonstrated that mice lacking Traf6 (a TNFR and IL-1/TLR family adapter protein) in T cells mount effector CD8 T cell responses to infection, but are unable to establish memory CD8 T cells. Our experiments revealed that this CD8 T cell intrinsic failure of memory development was tightly linked to the inability of Traf6-deficient CD8 T cells to initiate mitochondrial fatty acid oxidation, a pathway of lipid catabolism that fuels the TCA cycle. Based on our observations, and a panel of supportive preliminary data, we hypothesize that catabolic processes of energy generation are essential for the development of memory CD8 T cells after infection and that Traf6 plays a key role regulating this process. We will test this hypothesis through the following specific aims: 1) Determine how fatty acid metabolism regulates memory CD8 T cell development; 2) Determine the extent of Traf6-dependent regulation of memory CD8 T cell development; and 3) Establish that pharmacological manipulation of CD8 T cell metabolism can be therapeutic. The long-term goal of these studies is to facilitate the development of immunotherapies against infectious diseases. PUBLIC HEALTH RELEVANCE: Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. Nevertheless, the detailed underlying mechanisms regulating the generation and persistence of long-lived immunological memory remain largely undefined. Our proposal aims to build on our recent novel findings that strongly implicate a requirement for catabolic energy generating processes in the establishment of immunological memory and seeks to provide proof of principle that existing FDA approved drugs that are currently widely prescribed for metabolic and other disorders can be used to great effect to improve vaccine efficacy.